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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP status not known, non-guideline study, published in peer reviewed literature, limitations in design and/or reporting but otherwise adequate for assessment.

Data source

Reference
Reference Type:
publication
Title:
Petroleum hydrocarbon toxicity studies: V. Animal and human response to vapors of mixed xylenes.
Author:
Carpenter CP, Kinkead ER, Geary DJ, et al.
Year:
1975
Bibliographic source:
Toxicol Appl Pharmacol 33:543-558.

Materials and methods

Test guideline
Qualifier:
no guideline followed
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Reference substance name:
mixed xylenes
IUPAC Name:
mixed xylenes
Constituent 2
Reference substance name:
33-91
IUPAC Name:
33-91
Constituent 3
Chemical structure
Reference substance name:
Xylene
EC Number:
215-535-7
EC Name:
Xylene
Cas Number:
1330-20-7
Molecular formula:
C8H10
IUPAC Name:
xylene
Details on test material:
Mixed xylenes (m- 65.01%, o- 7.63%, p- 7.84% and ethylbenzene 19.27%).

Test animals

Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals or test system and environmental conditions:
No details reported

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: air
Details on inhalation exposure:
no details
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Gas chromatography.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
6 hours/day, 5 days/week
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0, 180, 460 or 810 ppm
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
0, 781, 1996 and 3515 mg/m3
Basis:
analytical conc.
No. of animals per sex per dose:
25 males
Control animals:
yes
Details on study design:
Groups of 25 male rats were assigned randomly to each of three graded levels of mixed xylenes or to the solvent- free air-control. Three rats from each group were killed for histological examination after 3 and 7 week intervals. Ten rats per group that survived 13 weeks were used for a challenge exposure to determine whether they had become more or less sensitive as a result of the repeated inhalation of vapour. The remaining rats were terminated after 13 weeks (65 days of exposure).
Positive control:
No

Examinations

Observations and examinations performed and frequency:
Measurements included body weight change and urine and blood analysis. Evaluations on blood included: haematocrit, total erythrocyte count, reticulocyte count, total and differential leucocyte counts, serum alkaline phosphatase (SAP), serum glutamic pyruvic transaminase (SGPT), serum glutamic oxalacetic transaminase (SGOT) and blood urea nitrogen (BUN).
Sacrifice and pathology:
At termination, the following tissues were taken for microscopic examination: adrenal, brain, pituitary, trachea, thyroid, parathyroid, lung, heart, liver, kidney, spleen, stomach, duodenum, pancreas, ileum, jejunum, colon, skeletal muscle, sciatic nerve, and bone marrow impression smear. All tissues were examined at each time point for the high dose and control groups, but for the low and intermediate dose only lung, liver, kidney, heart, spleen, adrenal, thyroid, parathyroid, trachea, oesophagus, and bone marrow impression smears were examined.
Other examinations:
Groups of ten rats per group that survived exposure over 13 weeks, were subjected to a 4-hr challenge period during which time they inhaled 29.0 mg/L (6700 ppm) of mixed xylenes. Their response was compared to the similarly handled control group and to 20 naive rats that were randomized from the same production lot as those under test but not subjected to daily handling.
Statistics:
No details

Results and discussion

Results of examinations

Details on results:
Two rats (one control and one low dose) died of extraneous pneumonic infections. All other rats gained weight normally. Minor differences in blood clinical chemistry and haematology were considered not to be adverse effects. Urinalyses performed before rats were sacrificed at 3, 7, and 13 wk revealed no abnormalities. No lesions ascribed to inhalation of mixed xylenes were found at any time point.

No statistically significant differences in median time to death were apparent following the challenge at the end of the study. No protective adaptive mechanism could be claimed as a result of exposure to concentrations as high as 3.5 mg/L (810 ppm) for 6 hr/day x 65 days (5 days /week for 13 weeks.

Effect levels

Dose descriptor:
NOAEC
Effect level:
>= 810 ppm
Sex:
male
Basis for effect level:
other: 3515 mg/m3

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The NOAEC of mixed xylenes for male rats exposed 6h/day for 5 days in each of 13 weeks was >=3515 mg/m3.
Executive summary:

Male rats were exposed 6h/day for 5 days in each of 13 weeks to 0, 0.77, 2.0 or 3.5 mg/L (0, 180, 460 or 810 ppm) mixed xylenes. The NOAEC was >=3515 mg/m3.